The present invention relates to new taxoids possessing strong antitumor activities, the precursors of these antitumor taxoids, and pharmaceutical compositions thereof.
Taxol (paclitaxel), a complex diterpene, is currently considered the most exciting lead in cancer chemotherapy. Paclitaxel possesses high cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. For example, paclitaxel has been approved by FDA in late 1992 for the treatment of advanced ovarian cancer and for breast cancer in 1994. Paclitaxel is currently in phase II and III clinical trial for lung cancer and other cancers.
Although paclitaxel is an extremely important xe2x80x9cleadxe2x80x9d in cancer chemotherapy, it is common that better drugs can be derived from naturally occurring lead compounds. In fact, French researchers have discovered that a modification of the C-13 side chain of paclitaxel brought about a new anticancer agent which seems to have antitumor activity superior to paclitaxel with better bioavailability. This synthetic compound was named xe2x80x9cTaxotxc3xa9re (docetaxel)xe2x80x9d, which has t-butoxycarbonyl instead of benzoyl on the amino group of (2R,3S)-phenylisoserine moiety at the C-13 position and a hydroxyl group instead of acetoxy group at C-10. Docetaxel is currently in phase II and III clinical trials in United States, Europe, and Japan, has shown excellent activity, especially against breast and lung cancers. 
A recent report on clinical trials of paclitaxel and docetaxel has disclosed that paclitaxel causes, e.g., nerve damage, muscle pain or disturbances in heart rhythm, whereas docetaxel provokes, e.g., mouth sores and a plunge in white blood cells. Other less serious side effects also exist for these two drugs. Therefore, it is very important to develop new anti-cancer drugs different from these two drugs which have fewer undesirable side effects, better pharmacological properties, improved activity against drug-resistant tumors, and/or activity spectra against various tumor types.
It is an objective of the present invention to develop such new anti-tumor agents of paclitaxel class, i.e., taxoids, which have distinct structural differences from those of paclitaxel and docetaxel.
It is an object of the present invention to provide a series of new taxoids bearing a 1-propenyl, 2-methyl-1-propenyl, 2-methylpropyl, or trifluromethyl radical at the C-3xe2x80x2 position instead of a phenyl group, and which possess strong antitumor activities with better therapeutic profile, in particular against drug-resistant tumors. One of the serious drawbacks of both paclitaxel and docetaxel is the fact that these two drugs possess only a weak activity against drug-resistant tumors, e.g., adriamycin-resistant breast cancer. The new taxoids of the present invention have shown not only stronger antitumor activities against human ovarian, non-small cell lung, colon, and breast cancers than those of the two drugs, but also exhibit more than one order of magnitude better activity against adriamycin-resistant human breast cancer cells than those of the two drugs. Multi-drug-resistance (MDR) is a serious issue in clinical oncology, and thus the new taxoid antitumor agents of this invention will serve as important drugs to overcome this problem.
One aspect of the invention is a taxoid of the formula (I): 
in which
R1 is a C3-C5alkyl or alkenyl or trifluoromethyl radical;
R2 is a C3-C5 branched alkyl radical;
R3 and R4 are independently selected from hydrogen and hydroxyl protecting groups including functional groups which increase the water solubility of the taxoid antitumor agent;
R5 represents a hydrogen or hydroxyl-protecting an acyl or alkoxycarbonyl or carbamoyl group;
R6 represents an acyl radical,
which are useful as antitumor agents or their precursors.
Preferably, R1 is selected from propyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methylbutyl, 2-methylbutyl, isobutyl, 2-methylethyl, 3-methylbutyl, 2-butenyl, or trifluoromethyl radicals;
R2 is selected from isopropyl, cyclopropyl, isobutyl, sec-butyl, 2-methylpropyl, 3-methylpropyl, tert-butyl, cyclobutyl, cyclopentyl, 1-ethylpropyl, or 1,1-dimethylpropyl radicals;
R5 is selected from hydrogen, C2-C6 acyl, C1-C6 alkoxylcarbonyl, C1-C6N-alkylcarbamoyl, or C1-C6 N,N-dialkylcarbamoyl radicals; and
R6 is selected from benzoyl, fluorobenzoyl, chlorobenzoyl, azidobenzoyl, cyclohexanecarbonyl, acryloyl, crotonoyl, 1-methylacryloyl, 2-methyl-2-butenoyl, or 3-methyl-3-butenoyl radical.
More preferably, R5 is selected from acetyl, propanoyl, cyclopropanecarbonyl, acryloyl, crotonoyl, 3,3-dimethylacryloyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, pyrrolidine-N-carbonyl, piperidine-N-carbonyl, morpholine-N-carbonyl, methoxycarbonyl, ethoxylcarbonyl, propoxylcarbonyl, butoxycarbonyl, cyclopentanecarbonyl, or cyclohexanecarbonyl radicals.
These new taxoids (I) are synthesized by the processes which comprise the coupling reactions of the baccatin of the formula (II): 
wherein G1 represents a hydroxyl protecting group, and R5 and R6 have been defined above, with the xcex2-lactams of the formula (III) 
wherein G is a hydroxyl protecting group such as ethoxyethyl (EE), triethylsilyl (TES), (tert-butyl)dimethylsilyl (TBS), and triisopropylsilyl (TIPS), and R1 and R2 have been defined above, in the presence of a base.
Another aspect of the invention is a taxoid of the formula (7): 
wherein
R1 is a branched or unbranched C3-C5alkyl or alkenyl radical, CF2H, or (S)-2,2-dimethylcyclopropyl; R8 is a C1-C4alkyl radical; and R7 is F, Cl, MeO, vinyl, Me, or N3.
R1 is preferably a branched or unbranched C4alkyl or alkenyl radical, more preferably CH2CH(CH3)2 or CHxe2x95x90C(CH3)2. R7 is preferably MeO or N3.
In one embodiment, R1 is CH2CH(CH3)2, R7 is MeO, and R8 is ethyl. In another embodiment, R1 is CHxe2x95x90C(CH3)2, R7 is MeO, and R8 is ethyl. In yet another embodiment R1 is CHxe2x95x90C(CH3)2, R7 is N3, and R8 is ethyl.
The invention also encompasses a method for treating tumors which comprises administering to a patient an effective amount of the taxoid of formula (7). Preferably, the method treats leukemia, melanoma, breast, non-small cell lung, ovarian, and colon cancers.
Yet another aspect of the invention is a pharmaceutical composition having antineoplastic activity containing the taxoid of formula (7) and a physiologically acceptable carrier.
A further aspect of the invention is a method for preparing a taxoid of formula (7), including coupling a baccatin of formula (5) with a xcex2-lactam of formula (6) in the presence of a base, 
wherein G and G1, which may be the same or different, each represents a hydroxyl protecting group, and R1, R7, and R8 are as defined for formula (7). Preferably, G and G1 are independently ethoxyethyl (EE), triethylsilyl (TES), (tert-butyl)dimethylsilyl (TBS), or triisopropylsilyl (TIPS).